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Lifting the Brain Fog: HCV and Depression in the DAA Era

Issue: April 2015

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On the surface, it might appear that there is little mystery surrounding the well-established association between hepatitis C virus and depression. Like most chronic disease states, hepatitis C virus can lead to anxiety, fatigue and restlessness, conditions that can then manifest as depressive disorder. Additionally, patients with hepatitis C have significant neuropsychiatric co-morbidities, including depression. Furthermore, interferon, which has been used for treatment of HCV, is notorious for causing a spectrum of neuropsychiatric adverse effects. A generation of patients with HCV dealt with depressive symptoms largely due to interferon-based therapies. The introduction of ribavirin brought improved outcomes, but past and current research indicate that ribavirin may also contribute to depressive symptoms.

In the current generation of direct-acting antiviral agents, a new wave of data is showing that, apart from remarkably high 12-week sustained virological response rates, novel treatments are demonstrating effectiveness in reducing depression and depressive symptoms in HCV. However, whether they will prove to be a cure for depression remains to be seen. The clinical community is attempting to untangle the physiological and treatment-related effects of HCV on the neurocognitive system in the DAA era.

Emanuela Apicella

“There are different mechanisms that contribute to the onset of psychiatric disorders in people affected by HCV, regardless of therapy with [interferon],” Emanuela Apicella, MD, specialist in psychiatry at Villa Miralago, Health Center for Eating Disorder, Varese, Italy, told HCV Next. “The etiology of psychiatric disorders is multifactorial and several factors can lead to the development of the manifestations: genetic factors, evolutionary factors, environmental factors and life events.”

Zobair M. Younossi, MD, MPH, chairman of the department of medicine at Inova Fairfax Hospital and vice president for research at Inova Health System in Falls Church, Va., is confident that adverse effects related to depression will likely not be seen in novel DAA regimens that are free from interferon and ribavirin. Another important issue related to HCV is the extrahepatic manifestation of HCV, which include fatigue and possibly depression. “Extrahepatic manifestation-induced issues may get better when we clear the virus,” he said.

However, this does not mean that experts have solved all of the problems surrounding HCV and depression. “Chronic HCV infection itself causes a surge in inflammatory cytokines. These cytokines can affect the brain inducing neuropsychiatric manifestations,” Younossi said. “The virus itself can cause changes in neurotransmitters in the brain. We will have to continue studying how those changes in the brain impact measures of mental health.”

Findings from ION-1

Younossi, along with Nezam H. Afdhal, MD, director of hepatology at Beth Israel Deaconess Medical Center, professor of medicine at Harvard Medicine School and an HCV Next Editorial Board member, and colleagues conducted a pilot study involving 14 treatment-naive patients with genotype 1 disease from the ION-1 study. Eligible participants received ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) with or without ribavirin for 12 or 24 weeks. The aim of the study was to investigate how best to take advantage of new DAAs in terms of improving neurocognitive outcomes in addition to curing HCV. The cohort was relatively young, with a high viral load, mild disease and active inflammation at the time of study entry, according to Afdhal.

“One thing we noticed from the literature is that patients with HCV have brain fog,” Afdhal told HCV Next. These studies suggest “there is viral bioreplication in the brain.”

Thirteen of 14 patients reached undetectable HCV RNA levels by 4 weeks, and SVR was reported in the entire cohort. By week 4, the researchers also observed alanine aminotransferase normalization.

Results of MR spectroscopy analysis demonstrated that the N-acetylaspartate/creatine ratio in the basal ganglia was significant at the time of SVR (P = .0134). “This suggests improved neuronal function,” Afdhal said. “This is consistent with gradual improvement after virus elimination.”

Other SVR12 findings showed that N-acetylaspartate/creatine ratio in the left basal ganglia increased among patients not receiving ribavirin (P = .0156) but did not change for patients assigned ribavirin (P > .05; P = .0181 between arms). “This suggests ribavirin negatively affects neurons or delays neuronal recovery,” Afdhal said.

A correlation was observed between changes in left basal ganglia metabolites and changes in the emotional function domain of the chronic liver disease questionnaire (CLDQ-HCV), according to MR spectroscopy results at 12 weeks. These results also indicated correlations between brain metabolism and overall mental health.

“These findings suggest a physiological reason for depression in HCV,” Younossi said. “If we suppress the virus, those symptoms improve, and we see changes in markers of brain metabolism. There is a direct viral effect that is more than just anxiety or fatigue.”

Zobair M. Younossi

“This exploratory study suggests that viral suppression can result in improvement in MR spectroscopic measures consistent with an overall improvement in neural health,” Afdhal added. “Furthermore, changes in the metabolite pattern captured by MR spectroscopy may be associated with changes in patient reported outcomes related to mental health.”

Afdhal noted, however, that the patient population included individuals with mild disease. “This study provides a rationale for treating patients with mild HCV,” he said.

Regimen may not Matter

Although most experts expect similar results from most novel therapies, Renata Fialho, clinical psychologist and PhD student at the University of Sussex, along with Richard Whale, MD, consultant psychiatrist at the Brighton and Sussex Medical School, and colleagues, found that treatment regimen — triple therapy vs. standard interferon regimens — did not affect depression-related outcomes in a cohort of 50 patients coinfected with HIV and HCV. Depression was identified with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) major depressive disorder and using the Hamilton Depression Rating Scale. Patient accrual occurred between 2010 and 2014 at a single center in England. The researchers aimed to evaluate the impact of acute vs. chronic HCV along with outcomes associated with classic HCV therapy compared with novel triple therapy.

Hamilton scores increased significantly from baseline to SVR (P < .001),according to the results. HCV treatment did not significantly affect outcome (or 0.83; 95% ci, 0.22-3.13), but chronic HCV infection increased the likelihood of transition to major depressive disorder compared with acute hcv (or 7.77; 95% ci, 2.04-29.54).

“Acute HCV patients appear to have a better response to hepatitis C treatment than those with chronic infection, but it is not clear why,” Fialho told HCV Next. “However, our study numbers were small and we only explored an HIV/HCV coinfection sample. At the moment, we are developing a new study looking at depression between acute and chronic hepatitis C cohorts. Chronic inflammation may render someone more vulnerable to depressive episodes through more persistent interruption of mood regulatory systems.”

“[Major depressive disorder] should be assessed before therapy initiation and monitored throughout treatment for any HCV treatment regime,” the researchers concluded. “Future research could usefully clarify mechanisms of [major depressive disorder] emergence and risk factors for this.”

“We can’t assume that interferon is the only cause, although it is a potent one. Clearly, more research is needed to better understand what type of depressive symptoms are associated with HIV/HCV coinfection and to what extent they interfere with treatment outcomes,” Fialho said.

Younossi built on this point, but in a somewhat more positive light. “We are not going to see depression caused by novel therapies,” he said. “However, how much better depression symptoms will become when we clear the virus remains to be seen. At the moment, we don’t know. We are currently trying to measure all patient reported outcomes, but these results are not fully published. There will be some improvement but how much is unclear.”

For Afdhal, the issue is one of viral replication. “We should see the same impact on depression with the ‘3D’ regimen,” he said, speaking of the combination of ombitasvir, paritaprevir, ritonavir and dasabuvir recently approved (Viekira Pak, AbbVie).

Inflammatory Condition

The fundamental area of research for Fialho and colleagues was the inflammatory model of depression in infectious diseases such as HIV and HCV infections. Their findings indicated that pro-inflammatory cytokines play a role in the onset of depression.

“While inflammation is neither absolutely necessary nor exclusive to depressive episodes, an association is evident in some individuals,” she said. “Inflammation can induce a constellation of behavioral symptoms that are typically associated with depressive behavior. These symptoms include anhedonia, fatigue, psychomotor, slowing appetite and sleep alterations.”

Other factors include increased sensitivity to pain and cognitive abnormalities, according to Fialho. “All of these factors were classically seen with interferon treatment,” she said. “However, the adjustment disorders characterized by the development of emotional or behavioral symptoms in response to a HCV diagnosis coexist and interact. A history of mental illness is a demonstrated vulnerability factor to an interferon-induced depressive episode. The final pathways to onset of low mood are likely interference with mood regulatory brain circuits and serotonin neurotransmission.”

Anxiety and Fatigue

Apicella and colleagues investigated the way in which chronic illness affects mental health. They reported increases in mood changes in anxiety along with the well-established poor responses to interferon therapy.

“What has been argued so far gives an account of how much weight may have, in a bio-psychosocial dimension, the diagnosis of HCV,” Apicella said. “The patient has, in fact, to live with a chronic medical condition, often without any physical and psychological resource to manage it. Illness, whatever it is, brings about such a big change of life to threaten the own sense of identity so that the disease can be lived with deep anguish, hate, anxiety and depression.”

Zalai and colleagues investigated the way in which insomnia, depression symptoms and fatigue-specific cognitions contribute to fatigue-related functional impairment in a cohort of 115 patients with chronic HCV from a tertiary clinic.

The rate of fatigue was 60%. Among those patients, perceptions of fatigue independently predicted adverse fatigue outcomes (beta = 0.114; 95% CI, 0.054-0.154). Clinically significant fatigue yielded a fourfold increase in the belief that HCV was causing fatigue.

Cost

Most of the news about the cost of novel DAA therapies is surrounded by controversy. For Afdhal, improvements in depression associated with these drugs may be a bright spot. “It is added value without any additional costs,” he said.

Nezam H. Afdhal

In another study, Younossi and colleagues investigated the way HCV affects the health-related quality of life for patients by causing fatigue, depression and anxiety. They aimed to investigate whether sofosbuvir/ledipasvir can improve these symptoms, thereby making them even more valuable. “Our review provides evidence that the new treatment regimens for HCV not only have high efficacy rates but are also associated with better patient-reported outcomes and cost per case of HCV cured,” they wrote. “Additionally, compared to other medical interventions, these new regimens are cost-effective from a societal perspective.”

There are a number of direct and indirect extrahepatic costs associated with HCV, according to Younossi. “HCV and its older therapies can cause fatigue and reduce work productivity, which has a negative economic impact on the individual and on the system,” he said, highlighting interferon and ribavirin as trouble spots for both clinicians and patients. “The cost of these new medicines may be high, but they have reduced cost burdens in other areas such as laboratory testing, side effect management and less provider visits. The price tag sounds big, but when you put it all together, it is not so big. Historically, everyone felt worse during treatment. With new regimens, there will be improvement in fatigue and some aspects of work productivity.”

Monitoring Depression

HCV clinicians have long had to be aware of depression, but Afdhal suggested that the constantly evolving clinical environment makes comprehensive knowledge of depressive disorder of paramount importance today. “N-acetylaspartate/creatine from MR spectroscopy may serve as a marker for neuronal recovery following therapy,” he said. “MRI blood flow imaging may help map spatial distributions of change.” He added that a fully powered placebo-controlled study is in progress.

Fialho suggested that monitoring should be incorporated in routine treatment with clear, safe treatment guidelines in place for when such episodes occur. “We have used the structured clinical interview for DSM-IV depressive disorder, which defines an important threshold to indicate the need for antidepressant treatment,” she said. “Many scales are available with clinical utility to explore depressive symptoms, such as the Hospital Anxiety and Depression Scale, Beck Depression Inventory, Montgomery–Asberg Depression Rating Scale, but we would encourage clinicians to use specific diagnostic tools to define such a threshold. The [Center for Epidemiological Studies Depression Scale-Revised] is often used in such samples and has reasonably good sensitivity and specificity for DSM-IV depressive episode.”

Regardless of how it is measured or monitored, Younossi came back to a basic reminder for those treating HCV. “The prevalence of depression in HCV is higher than in the general population,” he said.

It is because of this that Apicella urged clinicians to keep all options open. “There is not an exclusive cause, but a complex interaction of mechanisms that reinforces the idea that despite the advent of interferon-free regimens, the emergence of depression will remain prevalent,” she said.